1. Field of the Invention
The present invention relates to the diagnosis of cancer. In particular, this invention describes electromotive administration of dye substances into the bladder wall, with and without vasodilatation, for the localisation, or localisation and treatment, of occult cancerous sites in persons with diagnosed cancer of the bladder.
2. Description of the Prior Art
Bladder Cancer
Origins: Cancer of the bladder is usually multifocal in nature with malignant changes in normal tissues appearing in multiple sites. This situation has given rise to two schools of thought: 1) bladder cancer is multiclonal in origin or; 2) it is monoclonal in nature with facilitated spread laterally through bladder tissues and/or dispersion of viable cancer cells throughout the bladder cavity to seed at other sites. The -merits of these two hypotheses are still unresolved but, whichever is correct, the important aspect related to this invention is the frequent occurrence of multiple tumors at different sites within the bladder wall.
Treatment of Bladder Cancer: Following diagnosis of bladder cancer, there are three mainstays of therapy.
1. Transurethral Resection (TUR) where an endoscope is inserted into the bladder, sites of cancerous tissue are located visually and then resected and cauterised using an electrically heated wire loop. Patients return to operating rooms on a regular schedule and any subsequent cancers are also treated by TUR, a repetitive series of events that often goes on for years. The most appealing aspect of this particular therapy is that there is very little morbidity: patients are performing their usual activities the next day and the resected areas of bladder tissue are fully healed in 7-10 days. PA1 2. Radiotherapy is often employed when tumor penetration is too deep for successful TUR and there are debilitating long term side effects caused by generalised inflammation of the pelvic region. PA1 3. Operative procedures include the rare partial cystectomy and the more common total cystectomy (bladder removal). This latter procedure constitutes major debilitating surgery and also mandates some form of urinary diversion. PA1 1. Damage of any sort to the bladder mucosa, be it previous radiotherapy/chemotherapy, infection, or even mechanical trauma caused by overfilling with the dye itself, all give rise to false positive stains. PA1 2. Conversely, underfilling the bladder results in non uniform contact between the dye and bladder mucosa resulting in false negative areas of non-staining. PA1 3. Meeting the conflicting requirements of staining (pre) cancerous mucosa and non staining of normal urothelium is rendered even more uncertain by the physiological function of the bladder itself. PA1 4. The passive permeation revealed an overall low efficacy of penetration and staining of the bladder tissues. PA1 1. All drugs must be in ionized form and in aqueous solution (water, hydrogel). PA1 2. Positively charged drug ions are repelled from the anode and negatively charged drug ions are repelled from the cathode, into underlying tissues. PA1 3. Ionic transport of a solute in an electric field is described by the Nernst-Planck equation which states that: when a concentration gradient and electric field both exist, the ionic flux is the linear sum of the fluxes that would arise from each effect alone. (Planck, Keister et al: Planck M. uber die erregung von elektrizitat und warme in Elektrolyten Ann Phys Chem. 1890; 39:161-186. Keister J. C. et al. Ionic mass transport through a homogenous membrane in the presence of a uniform electric field. J Membrane Sci. 1986; 29:155-167). ##EQU1## where Di is the diffusion coefficient, .DELTA.Ci is the ionic concentration difference over a distance x, z is the valency and e the electron charge of the ion, E the electric field, k Boltzmann's constant and T is the absolute temperature. PA1 4. Petelenz et al (U.S. Pat. No. 4,915,685) teach that electrical transport of a specific ion is proportional to the product of the concentration, the mobility, and the charge (valency) of the particular ion; and inversely proportional to the concentrations, mobilities and valencies of all other ions in solution.
In addition to the above treatments, anticancer drugs are sometimes used either systemically, or by local instillation into the bladder. Administered systemically these drugs have dangerous side effects, sometimes causing death, and when administered locally into the bladder, many expected benefits do not materialize because of the physiological functions of the bladder itself.
Pathology of Bladder Cancer: The great majority of bladder cancers are described as transitional cell carcinomas arising from the normal transitional cell epithelium (urothelium) lining the interior of the bladder wall. The degree of penetration (spread) of these tumors is graded conventionally, Ta T.sub.1 T.sub.2 T.sub.3 T.sub.4, with Ta being the most superficial and T.sub.4 extending through and beyond the bladder wall into outlying tissues, as shown in FIG. 1. This Figure is a view of a longitudinal section of the bladder with the surrounding tissues. In particular the inner tissue is the urothelium (2), the second is the lamina propria (3) the third is the muscularis tissue (4) and the outermost is the perivescical tissue (5).
Malignant classification is also conventional, with G.sub.1 being the most benign and G.sub.3, G.sub.4 the most anaplastic and rapidly spreading. Hicks et al. (The ultrastructure and chemistry of the luminal plasma membrane of the mammalian urinary bladder: a structure with low permeability to water and ions. Philos Trans R Soc Lond (Biol). 1974; 268:23-38); demonstrated that cancer cells, both singly and in groups, display greater permeability to water and solutes than do the normal cells from which they arise; and the more anaplastic the cancer, the greater the permeability.
When viewed through an endoscope, many cancers may appear as papillomatous growths extending into the bladder cavity, as ulcers eroding the bladder wall or as combinations of the two. On direct viewing with an endoscope, flat (endophytic) cancers are often missed and carcinoma in situ (CIS) (6) which consists of discrete clumps of cancer cells buried in normal tissue, is almost always missed.
Blood Supply: Pertinent to this invention is the blood supply to cancerous tissue. As tumors grow they simply push normal blood vessels to one side and generate their own blood vessels by a process termed "angiogenesis". These new blood vessels are distinctly abnormal and form an interlacing network that becomes more abnormal the more anaplastic the cancers, and they take on the appearance of a series of interconnected lagoons in the highly malignant G.sub.3 and G.sub.4 tumor types. All of these abnormal blood vessels are of more or less fixed diameter, so that blood flow rate (Q.sub.B) through these same vessels responds to pressure changes only and is not responsive to the variety of physical (hot and cold) and chemical (drugs) agents that dilate and constrict normal blood vessels. Thus it is possible to vary, in a controlled manner, the differential in blood flow (.DELTA. Q.sub.B) between cancerous tissue and surrounding normal tissues by selective application for one or more vaso-active physical or chemical agents.